Research focuses on molecular messenger systems characterized in the Snyder laboratory which are substrates for actions of drugs of abuse. One involves a signaling cascade linking nitric oxide (NO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the ubiquitin E3-ligase Siah-1 and nuclear targets. A second deals with inositol hexakisphosphate kinase-2 (IPK6K2) in cell death and neurotoxicity, while a third addresses inositol polyphosphate multikinase (IPMK) and neural function. The NO-GAPDH-Siahl pathway was discovered as a cell death signaling system acting via nuclear p53. Recent work reveals a physiologic role wherein nitrosylated GAPDH, responding to neuronal growth factors, via Siah-1, degrades the histone methylating enzyme SUV39H1 leading to histone acetylation, gene transcription and dendritic outgrowth. Cocaine, in behavioral stimulant doses, activates this pathway. We will elucidate this pathway. IP6K2, a mediator of apoptosis, acts via p53. We are assessing how it distinguishes cell arrest/cell death via influences upon DNA protein kinase to activate p53. Its role in cocaine and MPTP actions is being investigated. IPMK is an inositol phosphate kinase and a PI3-kinase. We recently discovered that it is physiologically nitrosylated and acetylated, then binds to CBP and CREB, apparently activating CREB genetic programs. Cocaine administration activates IPMK nitrosylation/acetylation. We will explore its neural functions using newly generated IPMK knockout mice. We recentiy discovered that IPMK binds the small G-protein Rheb, known to activate mTOR. We previously showed that IPMK binds and stabilizes mTOR. We will investigate whether IPMK/Rheb coordinately regulate mTOR signaling in the brain in response to abusable drugs.

Public Health Relevance

Our research elucidates how the NO-GAPDH-Siah signaling cascade mediates neural messages including actions of cocaine. The work on IP6K2 and IPMK is similariy relevant, especially the novel potential role of nitrosylated/acetylated IPMK as a regulator of genetic programs impacted by cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA000266-41
Application #
8355358
Study Section
Special Emphasis Panel (ZDA1-EXL-T (02))
Project Start
Project End
Budget Start
2012-07-15
Budget End
2013-05-31
Support Year
41
Fiscal Year
2012
Total Cost
$389,153
Indirect Cost
$148,935
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51
Harraz, M M; Tyagi, R; Cortés, P et al. (2016) Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry 21:313-9
Guha, Prasun; Harraz, Maged M; Snyder, Solomon H (2016) Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade. Proc Natl Acad Sci U S A 113:1417-22
Scherer, Paul C; Ding, Yan; Liu, Zhiqing et al. (2016) Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc Natl Acad Sci U S A 113:3503-8
Fu, Xiuping; Shah, Aparna; Baraban, Jay M (2016) Rapid reversal of translational silencing: Emerging role of microRNA degradation pathways in neuronal plasticity. Neurobiol Learn Mem 133:225-32
Xu, Jin-Chong; Fan, Jing; Wang, Xueqing et al. (2016) Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8:333ra48
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
Rao, Feng; Xu, Jing; Fu, Chenglai et al. (2015) Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1. Proc Natl Acad Sci U S A 112:1773-8

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